Ready-to-use injectable pharmaceutical compositions comprising neostigmine and glycopyrrolate
The present invention provides stable, ready-to-use injectable pharmaceutical compositions, comprising the combination of neostigmine, glycopyrrolate, a stabilizing amount of one or more aminopolycarboxylic acids, and a pharmaceutically acceptable liquid vehicle. Other aspects of the invention relate to methods for making such compositions and methods of using such compositions for reversing the effects of non-depolarizing neuromuscular blocking agents. Preferably, the composition comprises neostigmine methylsulfate, glycopyrronium bromide, ethylenediaminetetraacetic acid (EDTA) and a pharmaceutically acceptable liquid vehicle, and is provided in a pre-filled, ready-to-use sealed container, such as a pre-filled syringe, suitable for intravenous administration.
1. A ready-to-use injectable pharmaceutical composition comprising (i) neostigmine or a pharmaceutically acceptable salt, solvate or hydrate thereof, (ii) glycopyrrolate or a pharmaceutically acceptable salt, solvate or hydrate thereof, (iii) one or more aminopolycarboxylic acids, and (iv) a pharmaceutically acceptable liquid vehicle, wherein the pharmaceutical composition is stable for at least 3 months at 25° C. and 60% relative humidity.
2. The pharmaceutical composition according to claim 1 , wherein the composition is provided in a sealed container selected from the group consisting of ampoules, vials and pre-filled syringes.
3. The pharmaceutical composition according to claim 1 , wherein the composition is in the form of a solution, suspension, or emulsion.
4. The pharmaceutical composition according to claim 1 , wherein the composition is suitable for subcutaneous, intravenous or intramuscular administration.
5. The pharmaceutical composition according to claim 1 , comprising neostigmine methylsulfate and glycopyrronium bromide.
6. The pharmaceutical composition according to claim 1 , wherein the one or more aminopolycarboxylic acids are selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA).
7. The pharmaceutical composition according to claim 6 , wherein the aminopolycarboxylic acid is EDTA.
8. The pharmaceutical composition according to claim 1 , comprising:
(i) neostigmine or a pharmaceutically acceptable salt thereof,
(ii) glycopyrrolate or a pharmaceutically acceptable salt thereof, and
(iii) a pharmaceutically acceptable liquid vehicle;
wherein the one or more aminopolycarboxylic acids comprise a stabilizing amount of ethylenediaminetetraacetic acid (EDTA).
9. The pharmaceutical composition according to claim 8 , wherein the composition has a pH ranging from about 3.0 to about 4.0.
10. The pharmaceutical composition according to claim 8 , wherein the composition is provided in a sealed container selected from the group consisting of ampoules, vials and pre-filled syringes.
11. The pharmaceutical composition according to claim 8 , wherein the composition is a solution, suspension, or emulsion.
12. The pharmaceutical composition of claim 8 , wherein the composition is suitable for subcutaneous, intravenous or intramuscular administration.
13. The pharmaceutical composition according to claim 8 , comprising neostigmine methylsulfate and glycopyrronium bromide.
14. The pharmaceutical composition according to claim 8 , wherein the neostigmine concentration is from about 0.5 mg/mL to about 5 mg/mL.
15. The pharmaceutical composition according to claim 8 , wherein the glycopyrrolate concentration is from about 0.1 mg/mL to about 1 mg/mL.
16. The pharmaceutical composition according to claim 8 , wherein ethylenediaminetetraacetic acid (EDTA) is present from about 0.1 mg/mL to about 5 mg/mL of the composition.
17. The pharmaceutical composition of claim 8 comprising:
(i) from about 0.5 mg/mL to about 5 mg/mL of neostigmine methylsulfate;
(ii) from about 0.1 mg/mL to about 1 mg/mL of glycopyrrolate bromide; and
(iii) about 0.5 mg/mL of EDTA.
18. The pharmaceutical composition of claim 17 comprising:
(i) from about 1 mg/mL to about 3 mg/mL of neostigmine methylsulfate;
(ii) from about 0.2 mg/mL to about 0.7 mg/mL of glycopyrrolate bromide; and
(iii) about 0.5 mg/mL of EDTA.
19. The pharmaceutical composition of claim 18 , comprising about 1 mg/mL of neostigmine methylsulfate, about 0.2 mg/mL of glycopyrronium bromide and about 0.5 mg/mL of ethylenediaminetetraacetic acid (EDTA).
20. The pharmaceutical composition of claim 18 , comprising about 2.5 mg/mL of neostigmine methylsulfate, about 0.5 mg/mL of glycopyrronium bromide and about 0.5 mg/mL of ethylenediaminetetraacetic acid (EDTA).
21. The pharmaceutical composition of claim 1 , wherein the level of Glycopyrrolate Impurity C is less than 1% (w/w) as measured by HPLC.